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Acute fatty liver of pregnancy (AFLP) and hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome are serious complications of pregnancy associated with significant maternal and perinatal morbidity and mortality. In previous reports, we have documented an association between AFLP and fetal deficiency of long-chain 3-hydroxyacyl coenzyme A dehydrogenase (LCHAD) [N. Engl. J. Med. 340 (1999) 1723-1731; JAMA 288 (2002) 2163-2166]. LCHAD activity resides in the alpha-subunit of the mitochondrial trifunctional protein (MTP), a complex protein that catalyzes beta-oxidation of long chain fatty acids. In all reported cases, the fetus carried a common alpha-subunit MTP mutation (G1528C, E474Q) on one or both alleles. However, the association between fetal LCHAD deficiency and the maternal HELLP syndrome has been limited. Here, we report a case history of a 27-year-old black female who underwent Cesarean section for placenta previa and fetal distress at 36 weeks gestation. The newborn was a healthy male child. Post-delivery, the mother developed severe HELLP syndrome with complications resulting in death of the patient. We used single strand conformation variance and nucleotide sequence analyses to screen DNA isolated from the mother and the newborn for mutations in the MTP alpha-subunit. The mother was heterozygous for a novel mutation (C1072A, Q322K) in exon 11 of the LCHAD domain of the MTP, while the fetal genotype was completely normal. We hypothesize that, in some cases, maternal heterozygosity for an MTP mutation maybe sufficient to cause the development of maternal liver disease without carrying an affected fetus. Combination of the metabolic stress of pregnancy and other environmental stresses may overwhelm the heterozygous mother's capacity for effective metabolism of long chain fatty acids, leading to an accumulation of potentially toxic fatty acid metabolites in the maternal circulation with subsequent damage to the maternal liver.

Hyperemesis gravidarum (HG) is the most severe form of illness within the spectrum of nausea and vomiting of pregnancy. Liver disease, usually consisting of mild serum transaminase elevation, occurs in almost 50% of patients with HG. While multiple risk factors have been proposed, the etiology and underlying mechanism of maternal liver disease associated with HG remains unclear. In this report, we hypothesize that impairment of mitochondrial fatty acid oxidation (FAO) plays a role in the pathogenesis of maternal liver disease associated with HG. We hypothesize that women heterozygous for FAO defects develop HG associated with liver disease while carrying fetuses with FAO defects due to accumulation of fatty acids in placenta and subsequent generation of reactive oxygen species. Alternatively, it is possible that starvation leading to peripheral lipolysis and increased load of fatty acids in maternal-fetal circulation, combined with reduced capacity of the mitochondria to oxidize fatty acids in mothers heterozygous for FAO defects, can also cause HG and liver injury while carrying non-affected fetuses. The rationale for this hypothesis is discussed.

Intestinal pseudo-obstruction can be caused by mitochondrial disorders. Understanding the association between genetic alterations in mitochondrial function and development of intestinal pseudo-obstruction may provide insight into the pathogenesis of this disorder. Although the association between mitochondrial DNA defects and pseudo-obstruction is documented, little is known about the relationship between mitochondrial beta-oxidation disorders, which are caused by defects in nuclear genes, and development of intestinal pseudo-obstruction. Mitochondrial beta-oxidation defects have emerged recently as an important group of recessively inherited inborn errors of metabolism with multiple phenotypes. Here we report the case history of a 25-year-old patient with mitochondrial trifunctional protein (MTP) deficiency, the eldest known living patient with this disorder. MTP is an enzyme complex that consists of 4alpha and 4beta subunits and catalyzes the last three steps in the beta-oxidation cycle. The patient's MTP deficiency is secondary to a compound heterozygosity for two mutations in the MTP beta-subunit. Over the past 5 years, the patient had worsening symptoms consistent with intestinal pseudo-obstruction associated with progressive skeletal myopathy and polyneuropathy. We hypothesize that impairment of mitochondrial beta-oxidation causes intestinal pseudo-obstruction secondary to accumulation of intracellular long chain fatty acids, activation of extramitochondrial fatty acid oxidation pathways, and generation of excessive reactive oxygen species leading to visceral myopathy.